This research proposal is designed to elucidate genetic influences on the susceptibility of animals to experimentally induced autoimmune encephalomyelitis (EAE). Rat EAE is one of the best models for the human illness, multiple sclerosis. In both rats and man, these diseases are mediated by T lymphocytes, which escape from the normal constraints of self-tolerance and respond to a component of the central nervous system called myelin basic protein. In both species, major histocompatibility complex (MHC) genes contribute to the susceptibility of individuals for disease; however, it is known that other background genes also play a significant role. The identity of the background genetic influences is currently the subject of intense investigation. An excellent model in which to study genes (other than MHC loci) that govern CNS autoimmunity is the Lewis/Lewis-resistant (LER) rat combination. The non-susceptible LER rat is virtually co- isogenic with the highly susceptible Lewis rat, yet they share the same (susceptible) MHC haplotype. Our preliminary evidence shows that the T cell receptor beta chain loci are radically different between the two strains, and thus we propose that the T cell receptor gene complex has a major effect on the differential EAE-susceptibility of these two strains. Our studies have the potential to provide a rationale for the poorly understood heritability of multiple sclerosis, and to provide further insight into the mechanism of pathogenesis of this disease.